Age associated losses of strength occur slowly over the adult lifespan. Most research has focused on what occurs in the elderly. However, the primary processes start at a much earlier age. In young and middle-aged workers, the early losses contribute to work related injuries and for some occupations, job performance. The causes of age related strength losses are multifactoral. Research has focused on age-associated loss of muscle, referred to as sarcopenia. While sarcopenia has been mainly studied in the elderly where the greatest changes in muscle mass and strength manifest, by age 50 the average individual has lost 10% of their maximal strength. Our goal is to understand the time course of strength loss, factors that contribute to the loss, the degree to which the exercise response differs between old and young individuals, and the forms of motivators and alternative exercise programs that might impact on the losses. We have used several different approaches to address these issues.[unreadable] First are descriptive studies using the Baltimore Longitudinal Study of Aging (BLSA). These studies focus on describing the characteristic losses in muscle strength, muscle mass, and physical functioning that occur with aging by examining the entire adult lifespan and their impact on function and longevity. We have previously demonstrated that declining muscle strength and rate of change of muscle strength are independent contributors to mortality in men when considering age, physical activity and muscle mass. We have further shown that muscle power, and speed of movement are further independent sarcopenic factors that contribute to longevity. The observations suggest that central nervous system processes are contributing to the importance of sarcopenia on longevity. [unreadable] Second, working with collaborators at the University of Maryland, we are examining genetic contributions related to muscle hypertrophy and strength. We have identified several genes that contribute to the inherited aspects of how much muscle and strength we have. As an example, we reported that IGF-II genotype is related to muscle strength but not muscle mass. This is consistent with the mortality data, where muscle mass and muscle strength have common and different effects on outcome. Also, we found that IL6 and CNTF genotype had some influence on body composition which impacts on sarcopenia. Ciliary neurotrophic factor (CNTF) was of particular interest as it is important for neuronal and muscle development, and we had previously reported that genetic variation in the CNTF gene is been associated with muscle strength. The effect of CNTF on nerve development, muscle strength, and body composition suggests that CNTF genotype may be associated with force production via its influence on motor unit size and firing patterns. In the past year, we examined whether CNTF genotype differentially affected motor unit activation in the vastus medialis with increasing isometric force during knee extension. We used surface and intramuscular electromyography with spiked triggered averaging to assess surface-detected motor unit potential (SMUP) area and mean firing rates (mFR) from identified motor units. The heterozygous CNTF G/A genotype was associated with smaller SMUP area motor units and lower mFR at higher force levels, and fewer but larger units at lower force levels than G/G homozygotes. The observations suggest that the two groups used motor units with different size and activation characteristics with increasing force generation at force levels utilized in daily activities. The observations suggest that genetic influences on nerve and muscle development impact on how the mature nervous system interacts with muscle, and in movement propagation. [unreadable] In other related work, we found that longer androgen receptor repeat in exon 1 in men is associated with higher testosterone blood levels and with greater levels of fat free mass. In the past year, we examined two genes related to myostatin, a negative regulator of skeletal muscle that plays a key role in muscle development and maintenance. However, DNA sequence variation within this gene has not been consistently associated with skeletal muscle mass nor muscle strength in humans. Follistatin and Activin RIIB (ACVR2B) are two myostatin related genes involved in the regulation/signaling of myostatin. We examined genetic variation in follistatin and ACVR2B to explore associations with skeletal muscle related phenotypes. Women heterozygous for ACVR2B haplotype groups 1 and 2 exhibited significantly less concentric quadriceps muscle strength than women homozygous for haplotype group 2 . No significant association was observed in men. Male but not female carriers of follistatin haplotype group 3 exhibited significantly less total leg FFM than non-carriers. The data indicate that the ACVR2B and follistatin loci may contribute to the inter-individual variation in skeletal muscle mass and strength. [unreadable] We are continuing to examine specific gene associations with muscle strength and muscle mass, with the hope of improved understanding of the genetic contributions to sarcopenia and mortality. In the coming year, we plan to expand the genetic work, as the BLSA completes a full genome scan. The main question will be to address the relationship between genetic composition and longitudinal changes in muscle strength and muscle mass across the adult life span. [unreadable] The third area of interest has been intervention studies to alter the time course of strength and muscle mass changes. In previous work we demonstrated that the exercise response to resistive training is very similar in young and old subjects. However, while the response to strength training may be similar by age, there are clear differences in muscle responsiveness as represented by gene expression, and body compostion change differences. In the past year, we published a study that assessed age and sex effects on muscle fibre adaptations to heavy-resistance strength training. Twenty-two young men and women (20-30 years old) and 18 older men and women (65-75 years old) completed 9 weeks of heavy-resistance knee extension exercises with the dominant leg 3 days week(-1); the non-dominant leg served as a within-subject, untrained control. Bilateral vastus lateralis muscle biopsies were obtained before and after ST for analysis of type I, IIa and IIx muscle fibre cross-sectional area (CSA) and fibre type distribution. ST resulted in increased CSA of type I, IIa and IIx muscle fibres in the trained leg of young men, type I and IIa fibres in young women, type IIa fibres in older men, and type IIx fibres in older women. These observations demonstrate that while both young and elderly individuals respond to strength training and lead to significant increases in strength and type II fibre CSA, age and sex influence specific muscle fibre subtype responses to the training.[unreadable] We have been interested in alternative strategies for exercise intervention. With Dr. Laura Talbot, we have examined two alternative exercise strategies using subjects with osteoarthritis of the knee. We found an increase in muscle strength in response to this passive activity, and a decline in knee pain immediately following the treatment (though not a sustained effect). The second approach was to use home based pedometer driven motivational program resulted in improved walking, increased knee extensor strength, and modest functional improvements. We are now beginning a study to examine whether the use of electromyostimulation can positively impact the course of recovery from traumatic war-related below the knee amputation. During recovery and rehabilitation, quadriceps muscle strength declines following traumatic amputation. NMES may offer a passive form of exercise that can maintain strength during this time period.